These investigations will attempt to show that: (1) severe burn injury produces overwhelming complement (C') activation, with generation of cleavage products, (2) cleavage products activate neutrophils (PMN's) releasing toxic products (lysozyme, prostaglandins, superoxide), (3) these C' and/or PMN products result in vascular permeability and damage, ultimately resulting in burn shock and shock lung, (4) pharmacologic agents may be used to inhibit these processes, (5) the resulting C' deficiency contributes to burn sepsis. Preliminary studies from my laboratory suggest that burns do produce profound C' activation, and that this activation proceeds by the alternative complement pathway, and prior C' reduces mortality from 65% to 10% in the first 24 hours after burns in mice. Further study is necessary to demonstrate the nature and pathway of activation, the role of C5a, and/or PMN's, the role of burn-activated C' in shock and shock lung, the utility of C' and/or PMN inhibitors in reducing early injury and death, and the role of C' deficiency in burn sepsis. In vitro studies in animals and humans will establish the nature and pathway of burn initiated C' activation, and involvement of activated PMN's and superoxide. Functional, immunodiffusion and crossed immunoelectrophoretic analysis will be performed on serum; bioassay for C5a will be performed on plasma, and PMN superoxide production will be assayed. In vivo studies, using C' deficient animals (cobra venom treated; C5 deficient inbred), as well as animals treated with C' and/or PMN inhibitors (high dose heparin, propamidine, lidocaine, etc.), will be used to correlate C' and PMN function with hemodynamics, pathology, pulmonary edema, local ischemia, infection and mortality. The goal is development of new therapeutic strategies.